Neuropathy is a painful and debilitating condition that affects over 15 million Americans. Surprisingly over 30% of patients are labeled as idiopathic even after an extensive evaluation. For those patients with the most common cause of neuropathy, diabetes, glucose control remains the only effective treatment. Unfortunately, greater than 40 percent of patients with diabetes will develop neuropathy despite good glucose control. These observations highlight the need to identify modifiable risk factors for neuropathy that may be the cause of idiopathic neuropathy and the factors that in addition to high serum glucose lead to diabetic neuropathy. Metabolic syndrome components may be these important modifiable risk factors in neuropathy. This syndrome is comprised of multiple cardiovascular risk factors that tend to cluster together. Past observational studies have implicated one or more of these components in the development of neuropathy, but these studies have suffered from significant design limitations. Most studies were only cross-sectional in design and focused only on diabetic populations. Furthermore, these studies did not apply a standardized definition of neuropathy, and case classification was often based on one diagnostic test. In this career development award, we propose to quantify the impact of the metabolic syndrome on neuropathy and to determine which metabolic syndrome components are associated with neuropathy in two specific aims. In aim 1, we will compare the prevalence of neuropathy in a metabolic syndrome cohort with lean controls by utilizing extensive neuropathy phenotyping. In aim 2, we will employ cross-sectional and longitudinal designs to identify which metabolic syndrome components are associated with neuropathy. The cross-sectional design has the advantage of applying clinical neuropathy outcome measures prior to any intervention. The advantage of the longitudinal component is that we can investigate the relationship of the dynamic changes in metabolic syndrome components after a diet and exercise regimen with changes in neuropathy outcome measures. The overall goal of this project is to identify modifiable risk factors for the development of neuropathy that will lead to interventional clinical trials to prevent and/or treat neuropathy. This proposal is essential to my career development. I will become an independent clinical researcher with expertise in neurologic complications from endocrinologic disease states. The biostatistician and epidemiologic formal training and practical experiences will set the stage for successful completion of not only this project, but also of future investigations. The clinical trial component of my career development will allow me to take the results from this study and seamlessly transition into interventional studies that will lead to new treatments for patients with neuropathy. Drs. Eva Feldman and Charles Burant are ideally suited as mentors for this project with their complementary expertise in neuropathy and metabolic phenotyping. The vast resources of the University of Michigan, including the Neuropathy Center, the Investigational Weight Management Clinic, the Michigan Institute for Clinical and Health Research, and the school of Public Health, will significantly contribute to the successful completion of this proposal.